Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE-and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

Objective. Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-␣ levels in the CSF. Studies have shown that AGS is an autosomalrecessive disease linked to mutations in 5 genes, encoding the 3 -repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A-C), and sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease.Methods. Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies.Results. In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS.Conclusion. These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by Supported by the Deutsche Forschungsgemeinschaft (DFG grant LE 1074/3-1).

SUMMARYPurpose: To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors. Methods: We retrospectively studied the clinical courses and outcomes of 52 children with refractory epilepsy who underwent hemispherotomy in the Epilepsy Center Freiburg between 2002 and 2011. Key Findings: Mean age at epilepsy onset was 1.8 years (range 0-8 years) and mean age at surgery was 6.7 years (range 6 months-18 years). The underlying etiology was congenital in 22 (42%) children, acquired in 24 (46%), and progressive in 6 (12%). At final follow-up of 1-9.8 years (mean 3.3), 43 children (83%) were seizure-free. Seizure outcome was not correlated to etiology, with the exception of hemimegalencephaly that was linked to poor seizure control. Presurgical development was impaired in all but one child. Postsurgical development highly correlated with presurgical development. Patients with acquired or progressive etiology, later epilepsy onset, and subsequent later surgery exhibited higher presurgical developmental status that substantially determined postoperative developmental outcome. Improved postsurgical development was determined by acquired etiology and seizure freedom off antiepileptic drugs. Significance: In our study, most of the selected children and adolescents achieved seizure freedom, including those with congenital etiology. Developmental outcomes, however, were superior in patients with acquired etiology and older age at surgery, underscoring that it is never too late to reap the benefits of this procedure in terms of both epilepsy and development.

Our study demonstrates that epilepsy surgery in very young children is safe as well as efficient regarding long-term seizure freedom and antiepileptic drug cessation in selected candidates. Longer epilepsy duration is the only modifiable predictor of impaired adaptive and cognitive development, thus supporting early surgical intervention.

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Completeness of resection predisposes to favorable outcomes regarding seizure alleviation. Whereas cognitive functioning deteriorates with time in glioneuronal tumor-related refractory epilepsy, surgery is linked to improvement rather than to deterioration on a group level.

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Mesial temporal sources are presumed to escape detection in scalp electroencephalographic recordings. This is attributed to the deep localization and infolded geometry of mesial temporal structures that leads to a cancellation of electrical potentials, and to the blurring effect of the superimposed neocortical background activity. In this study, we analyzed simultaneous scalp and intracerebral electroencephalographic recordings to delineate the contribution of mesial temporal sources to scalp electroencephalogram. Interictal intracerebral spike networks were classified in three distinct categories: solely mesial, mesial as well as neocortical, and solely neocortical. The highest and earliest intracerebral spikes generated by the leader source of each network were marked and the corresponding simultaneous intracerebral and scalp electroencephalograms were averaged and then characterized both in terms of amplitude and spatial distribution. In seven drug-resistant epileptic patients, 21 interictal intracerebral networks were identified: nine mesial, five mesial plus neocortical and seven neocortical. Averaged scalp spikes arising respectively from mesial, mesial plus neocortical and neocortical networks had a 7.1 (n = 1,949), 36.1 (n = 628) and 10 (n = 1,471) µV average amplitude. Their scalp electroencephalogram electrical field presented a negativity in the ipsilateral anterior and basal temporal electrodes in all networks and a significant positivity in the fronto-centro-parietal electrodes solely in the mesial plus neocortical and neocortical networks. Topographic consistency test proved the consistency of these different scalp electroencephalogram maps and hierarchical clustering clearly differentiated them. In our study, we have thus shown for the first time that mesial temporal sources (1) cannot be spontaneously visible (mean signal-to-noise ratio -2.1 dB) on the scalp at the single trial level and (2) contribute to scalp electroencephalogram despite their curved geometry and deep localization.